Effects of L-Citrulline Supplementation and Aerobic Training on Vascular Function in Individuals with Obesity across the Lifespan

Abstract

Children with obesity are at higher risk for developing cardiometabolic diseases that once were considered health conditions of adults. Obesity is commonly associated with cardiometabolic risk factors such as dyslipidemia, hyperglycemia, hyperinsulinemia and hypertension that contribute to the development of endothelial dysfunction. Endothelial dysfunction, characterized by reduced nitric oxide (NO) production, precedes vascular abnormalities including atherosclerosis and arterial stiffness. Thus, early detection and treatment of cardiometabolic risk factors are necessary to prevent deleterious vascular consequences of obesity at an early age. Non-pharmacological interventions including L-Citrulline (L-Cit) supplementation and aerobic training stimulate endothelial NO mediated vasodilation, leading to improvements in organ perfusion, blood pressure, arterial stiffness, atherosclerosis and metabolic health (glucose control and lipid profile). Few studies suggest that the combination of L-Cit supplementation and exercise training can be an effective strategy to counteract the adverse effects of obesity on vascular function in older adults. Therefore, this review examined the efficacy of L-Cit supplementation and aerobic training interventions on vascular and metabolic parameters in obese individuals.

Keywords: L-Arginine; L-Citrulline; aerobic training; children; nitric oxide; obesity; vascular function.

Figure 1

Obesity and endothelial dysfunction. Adipocyte hypertrophy leads to release of FFA, leptin, resistin, TNFα and IL-6 into the vascular wall, promoting inflammation, while anti-inflammatory adiponectin secretion is reduced. Proinflammatory adipokines and hyperglycemia induce the production of ROS, which by uncoupling eNOS leads to reduced NO synthesis and bioavailability for vasodilation, promoting a vasoconstrictor state. Cardiometabolic risk factors contribute to endothelial dysfunction, characterized by a reduced NO bioavailability, which promotes atherosclerosis and arterial stiffness and development of CVD. FFA: Free fatty acids; TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin-6; ROS: Reactive oxygen species; NO: Nitric oxide; eNOS: endothelial NO synthase; CVD: Cardiovascular disease; ↑: Increase; ↓: Decrease.

Figure 2

Vascular effects of aerobic training and L-Citrulline supplementation in individuals with obesity. Supplemented L-Cit is mainly metabolized in the kidneys and converted to arginosuccinate by ASS and then to L-Arg by ASL. De novo synthesized L-Arg is released into systemic circulation. In endothelial cells, eNOS catabolizes L-Arg to NO and L-Cit. NO diffuses into the VSMC where it stimulates sGC and subsequently activates cGMP, leading to a decrease in intracellular calcium concentrations and vasodilation. Aerobic training activates eNOS and reduces oxidative stress by increasing antioxidant capacity. Thus, L-Cit supplementation and exercise training decrease atherosclerosis, arterial stiffness, and blood pressure by improving endothelial function. L-Cit: L-Citrulline; L-Arg: L-Arginine; ASS: Arginosuccinate synthetase; ASL: Arginosuccinate lyase; eNOS: Endothelial nitric oxide synthase; NO: Nitric oxide; VSMC: Vascular smooth muscle cells; sGC: Soluble guanylyl cyclase; cGMP: Cyclic guanosine monophosphate; ↑: Increase, ↓: Decrease.

Figure 3

Cardiovascular improvements with L-Citrulline supplementation and moderate-to-high intensity aerobic training. In children and adolescents with obesity and cardiometabolic alterations, aerobic training helps to improve blood pressure (SBP), endothelial function (NO and FMD), atherosclerosis (cIMT), arterial stiffness (baPWV), dyslipidemia (triglycerides, total cholesterol, LDL-C and HDL-C), and body composition (waist circumference and total body fat). L-Cit supplementation in adults with cardiometabolic alterations helps to improve NO production, blood pressure (SBP), arterial stiffness (baPWV and faPWV), dyslipidemia (triglycerides and HDL-C), glucose control (insulin, glucose and HOMA-IR) and body composition (total body fat and lean mass). L-Cit: L-Citrulline; SBP: systolic blood pressure; NO: nitric oxide; FMD: flow-mediated dilation; cIMT: intima–media thickness; baPWV: brachial–ankle PWV; LDL-C: LDL cholesterol; HDL-C: HDL cholesterol; faPWV: femoral–ankle PWV; HOMA-IR: homeostatic model assessment-insulin resistance; ↑: Increase; ↓: Decrease.